Oxidation of amino acids by reactive oxygen species is considered to accelerate aging. The amino acid methionine is readily oxidized to form two epimers of methionine sulfoxide, methionine-R-sulfoxide (met-R-O) and methionine-S-sulfoxide (met-S-O). The enzyme methionine sulfoxide reductase A (MSRA) reduces met-S-O while the enzyme methionine sulfoxide reductase B (MSRB) reduces met-R-O. Multiple forms of MSRA and MSRB that differ in tissue and subcellular distributions are now known. Increasing evidence suggests that methionine oxidation may be an important determinant of the time course of normal aging. However, there is no systematic information available how the met-R/S-contents and MSRA/B activities change with age. Furthermore, it is not known whether different MSR forms play similar roles in aging. Using the model organism Drosophila, the study proposed here will provide a comprehensive view of the roles of methionine oxidation and MSRs in normal biology of aging. Age-dependent changes in the oxidized methionine contents and MSR activities in different tissues and subcellular fractions are systematically measured. Different forms of MSRs are overexressed in different tissues and subcellular regions to compare their efficacies in lifespan extension and delaying the onset of decline in the physical activity level and reproductive vigor. Furthermore, gene expression profiles in the long-living MSRA flies are systematically compared with those of control flies. The study will also test whether a food supplement, S-methyI-L-cysteine, could act to extend the animal lifespan by participating in the reversible methionine oxidation cycle involving the MSR system. The results expected should prove valuable in designing interventions to extend lifespan.